Epidemiological investigations into chronic inflammation using the novel biomarker Glycoprotein Acetyls

Chronic inflammation describes a state of long-term inflammation where levels of acute-phase proteins and cytokines are elevated over months to years. Epidemiological studies have provided evidence for the relationship between inflammation and adverse health outcomes, ranging from mental health disorders such as depression to physical health outcomes such as cardiovascular disease and even mortality. Additionally, studies have shown that genetic and environmental factors can influence levels of chronic inflammation. Given the proven detrimental outcomes of chronic inflammation, it is a public health concern to better understand its causes and consequences. In this thesis, I investigated whether Glycoprotein Acetyls (GlycA), a novel biomarker of chronic inflammation was more stable in the short and long term compared to C-reactive protein (CRP), an acute phase protein often studied as a marker of inflammation. I also explored several potential causes and consequences of chronic inflammation (as measured by GlycA), including adverse childhood experiences (ACEs), the mental health disorder depression, depressive symptoms and levels of circulating polyunsaturated fatty acids. I used data from two UK population-based studies: the Avon Longitudinal Study of Parents and Children and; UK Biobank. Where possible, I triangulated findings from multivariable models with Mendelian randomization analyses in order to overcome biases such as confounding and reverse causation. My findings suggest that GlycA behaves similarly to the biomarker CRP in response to pro-inflammatory factors, but that it is more stable than CRP over the long-term. I found that ACEs have a pro-inflammatory effect, but that this effect appears to only emerge in mid-adulthood. Contrary to previous literature, I did not find that inflammation causally increases levels of depression, instead my findings suggest that genetically determined depression causally increases levels of GlycA. I also found that genetically determined omega-3 fatty acid levels, which are posited to reduce inflammation, causally increase levels of CRP and GlycA, although this effect attenuated to the null when controlling for genetically determined omega-6 fatty acids. Finally, I found that genetically determined omega-6 fatty acids causally increase levels of CRP and GlycA and this effect was maintained when controlling for genetically determined omega-3 fatty acids. Results from my thesis suggest that several factors that occur across the life-course can influence levels of GlycA. My findings also highlight the importance of triangulation and replication in research given that, when using GlycA as a measure of inflammation, some of my findings contradict previously published and accepted inflammation-related relationships